The diagnosis and management of primary autoimmune haemolytic anaemia

• DOI: 10.1111/bjh.14478
• Publication Date: 2016-12-24T02:42:52Z
• Authors: Quentin A. Hill; Robert Stamps; Edwin Massey; John D. Grainger; Drew Provan; Anita Hill
• Keywords: Primary (astronomy)

The objective of this guideline is to provide healthcare professionals with guidance on the management patients primary autoimmune haemolytic anaemia (AIHA). may not be appropriate every patient and in all cases individual circumstances dictate an alternative approach. Attempts categorise (AIHA) define its response treatment vary considerably published literature. Author defined criteria have been used guideline, but limits study comparisons will contributed differences reported outcome. investigation diagnosis adult paediatric AIHA are considered together. Guidance then followed by a section AIHA. Recommendations based systematic review English language literature from January 1960 October 2015 (see Appendix S1 for further details). Although recommendations unchanged, expanded version available as S2. Grading Assessment, Development Evaluation (GRADE) nomenclature was evaluate levels evidence assess strength recommendations. GRADE specified British Committee Standards Haematology (BCSH) pack (http://www.bcshguidances.com/BCSH_PROCESS/42_EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION.html) working group website http://www.gradeworkinggroup.org selected representative UK-based experts Review manuscript performed BCSH General Task Force, Executive sounding board Society (BSH). This compromises 50 or more members BSH who reviewed commented content applicability UK setting. decompensated acquired haemolysis caused host's immune system acting against own red cell antigens. incidence approximately 1 per 100 000/year (Pirofsky, 1975; Klein et al, 2010). It can occur at any age rises increasing age. Serologically, divided into warm type (65%), cold (29% haemagglutinin disease [CHAD], 1% paroxysmal haemoglobinuria) mixed (5%). Approximately half (idiopathic) secondary associated disorders (Table 1). Patients present symptoms (weakness 88%, dizziness 50%, dyspnoea 9%), (jaundice 21%, dark urine 3%) underlying disorder 1975). Without disease, examination unremarkable reveal mild pallor splenomegaly. Less often, severe leads hepatosplenomegaly, haemoglobinuria signs heart failure (Packman, 2008). Cold (CHAD) chronic clonal disorder, usually occurring middle elderly. Cold-induced acrocyanosis (dusky blue appearance toes, fingers, nose tip ears) Raynaud phenomenon 40‒90% (Berentsen 2006; Swiecicki 2013). Secondary CHAD self-limiting, example following childhood infection. With different natural history, has also termed agglutinin syndrome & Tjonnfjord, 2012). Paroxysmal (PCH) typically transient, presenting 1–2 weeks after upper respiratory tract infection other illness acute fever, abdominal, back leg pain (Gehrs Friedberg, 2002). Haemolysis intravascular settles over several weeks. When presents suspected AIHA, three questions should considered. Is there haemolysis; what AIHA? However, confounding factors these laboratory tests highly specific. Some parameters normal, especially compensated haemolysis. differential shown Table 2. A positive direct antiglobulin test (DAT) indicates presence immunoglobulin (Ig)G, IgM, IgA complement (usually C3d) bound membrane. In haemolysis, suggests aetiology clinical assessment required before made. Typically monospecific anti-IgG anti-C3d antibodies initial screening help determine DAT specific wide range non-haemolytic states, possibly through passive deposition immunoglobulins complexes; examples include liver infection, malignancy, systemic lupus erythematosus (SLE), renal drugs such intravenous (IVIg) antithymocyte globulin. Rarely, negative tube DAT, due low affinity antibody, antibody tested (e.g. IgA-only AIHA). gel column agglutination method sensitive that less prone error than conventional (Fayek diagnosed 3% testing card using elution technique (Sachs 2006). Donath-Landsteiner children haematuria discussed under investigations. DAT-negative generally milder steroid responsive. most relevant investigate cause 3. reticulocytopenia phase AIHA; haematinic deficiency, marrow infiltration, aplastic parvovirus B19 if it present. Further serological warm, CHAD, PCH) approach differs. Finally, requires blood, investigations needed exclude alloantibodies identify units suitable transfusion. adults, two 7 ml EDTA samples sufficient investigation. clotted sample PCH DIIHA. If C3 ± IgG i)DAggT insignificant CAs ii)age <18 years atypical serology Typical characteristics subtypes 4. autoantibody specificity sometimes identified, does predict outcome (Issitt, 1985). autoantibodies IgG) bind cells optimally vitro 37°C. anti-C3 reagents, would for: only (35%), + (56%) (9%) when consistent picture IgG, both, clinically significant reactive excluded (Fig IgM) 4°C. only, 21–28% Furthermore, 7–31% C3-only CHAD. Marked blood film classically seen PCH. Milder occurs polyclonal agglutinins (CAs) spread room temperature. Up 35% 20°C (Petz Garratty, 1980). must therefore distinguished CAs. thermal amplitude (the maximum temperature which binds vitro) <25°C. At 4°C, CA titre dilution <1:64 rarely exceeds 1:256. >1:500 4°C ≥30°C (but 25°C suspended saline rather 30% bovine albumin). Defining absolute cut-off difficult exceptions. high antibody. supportive where diagnostic uncertainty exists. term 'primary' describe without infective no radiological lymphoma. immunophenotyping, majority bone lymphoproliferative circulating IgM monoclonal paraprotein (Berentsen, 2011). detected serum electrophoresis immunofixation >90% 2006) kept 37°C until separated remain cells. All appropriately constituted haemato-oncology multidisciplinary team (National Institute Clinical Excellence, 2003). biphasic causes complement-mediated lysis raised. only. There agglutination, spherocytes erythrophagocytosis neutrophils film. Reticulocytopenia common early PCH, evolving reticulocytosis recovery. test. technically (Sokol 1999) false results avoided indirect method. Testing specialist required. excluded, either haemoglobinuria, cold-associated symptoms, features old. some DAT. Mixed combination least 30°C. C3. <1:64). do appear 1983; Shulman C3, ≥30°C, absence typical pathway illustrated Fig 1. screened (DAggT) local transfusion laboratory; saline-suspended normal agglutinated patient's incubation 30–60 min (Petz, positive, distinguish Samples titres transportation. As challenging, received ethylenediaminetetra-acetic acid (EDTA)-anticoagulated warmed water bath h algorithm 1) guide always straightforward. advice reference final limitation (cold titres, test) current External Quality Assurance (EQA) scheme. conducted laboratories performing regular basis. Investigation guided sections 6·5 7·13 recent guidelines pre-transfusion compatibility procedures (Milkins main aims ABO, Rh K status alloantibodies, Full take 4–6 2004). alloantibody (most commonly K) rare history previous pregnancy life threatening, matched delaying full completed. use warmer ensuring environment rational although benefit limited. These options emergency situation: Evidence case series 40% respond IVIg 0·4–0·5 g/kg/day 5 days responders maintained their Hb ≥3 (Flores 1993). Response predicted pre-treatment Hb; accepted Department Health short <60 g/l higher co-morbidities) temporising measure prior splenectomy (Wimperis plasma exchange largely limited reports temporary. Plasma while attempting control therapies, immunosuppression (Von Baeyer, 2003; Szczepiorkowski experience dose methylprednisolone reports. Methylprednisolone role fulminant risk serious infections increase (Everett Bay 2007). transfusion-dependent responded require urgent splenectomy. vaccinated 2 splenectomy, deferred 14 post-splenectomy functional responses improved (Davies critically ill deemed unfit severity lack transfuse), documented success partial splenic embolisation. overall steroids disappointing rates 14–69% larger series. Responses often partial, cannot sustained unacceptably dose. given therapeutic options, trial prednisolone mg/kg/day rescue therapy. were 4/6 transient 2008) like stabilising conjunction Agglutination within separator tubing, active extracorporeal circuit need Daily day 1–1·5 times volume albumin recommended (Szczepiorkowski VTE important morbidity mortality likely active. one (defined <85 g/l), occurred 6/28 (21%), significantly thromboprophylaxis (Hendrick, another study, 8/40 (20%): seven had uncompensated (Hb 41–89 g/l) 6 outpatients (Lecouffe-Desprets 2015). Prior widespread practice folic supplementation, numerous megaloblastic folate deficiency anaemia. peptic ulcer (PUD) general population 0·1%, gastrointestinal complications 2·2- 4·2-fold corticosteroids. Other age, ulcer. receiving corticosteroids, highest those concomitant non-steroidal anti-inflammatory (NSAIDS) aspirin PUD risk. Osteoporotic (particularly vertebral) fracture up 30–50% adults long glucocorticoids (Rizzoli Calcium vitamin D supplements (typically 1200–1500 mg calcium 800–1000 D) reduce loss corticosteroids (Weinstein, 2011; Rizzoli well-performed studies, mineral density increased bisphosphonates. Postmenopausal women men aged ≥50 starting anticipated duration months ≥7·5 mg/day osteoporotic additional bisphosphonate (Grossman 2010; Hansen Lekamwasam summarised For many patients, condition goal therapy minimal side effects. Morbidity poorly understood, death uncontrolled still occur, relative contribution significant. 80% equivalent 60–100 two-thirds achieve complete remission (CR). 21 failure. responding incremental taper begin, once >100 3 weeks, reducing 20–30 month. 33 cases, relapse tapered ≤10 stopped (Dussadee 20% discontinued. maintain acceptable maintenance <15–20 mg, effects steroids, second line Dexamethasone Data suggest dexamethasone superior (Meyer 1997; Ionita best-studied efficacious treatments rituximab 70% even rituximab. Following refractory relapsing rate appears (Rivero 1979; Barcellini 2014; Roumier 2014). Given significance course effective well-tolerated steroid-sparing agent consideration 100% [n = 17/17 (Bussone 2009); n 11/11 (D'Arena 2007); 14/14 (Barcellini 2012)]. including 79% CR 42% (Reynaud adversely affect outcome, better shorter prospective randomised first compared monotherapy (Birgens 12 months, 75% vs. 36% (P 0·003) respectively. Median time 3–6 (range 2–16 weeks). unknown 14–25% median 15–21 2009; 2012) 50% 30 (Maung Rituximab well tolerated neutropenia, infusion-related reactions 2009) reported. Reactivation hepatitis B virus (HBV) potentially fatal complication pre-administration HBV surface antigen core (https://www.medicines.org.uk/emc/medicine/2570; last accessed April Progressive multifocal leucoencephalopathy (Carson 2009). standard regimen 375 mg/m2 weekly four consecutive achieves profound suppression (Provan 4 prednisolone, 2012), produced comparable rates. earlier stage studies therapy, variable definitions follow-up limit comparison. listed alphabetically so show preference particular 60% azathioprine 100–200 (Worlledge 1968), 2–2·5 1975) unstated number achieving independence unclear. Thiopurine methyltransferase (TPMT) prevents metabolism commencing Case small efficacy Where specified, ciclosporin mg/kg/day. Six out (3 treated line) danazol 200 3–4 times/day, added (Ahn later 13 77% (Ahn, 1990). 3/3 daily (Manoharan, 1987). Small Most multiple therapies MMF 500 twice daily, titrated g daily. took months. Larger unselected 50–85% (improved sensitivity steroids). combined, 71% (61/86) (Chertkow Dacie, 1956; Dausset Colombani, 1959; Allgood Chaplin, 1967; Ly Albrechtsen, 1981; Akpek (31/74). few surgery slower (5–6 months) third suggested relatively uptake good supported subsequent scanning fallen routine practice. Vaccinations re-vaccination schedule latest (Public England, 2013) guidelines. Prophylactic antibiotics started postoperatively provided discharge 2% develop 90 (Thomsen Postoperative portal vein thrombosis (PSVT) anaemia, 8% (4/47) (van't Riet 2000). Extended molecular weight heparin (LMWH) prophylaxis proposed grounds (Mohren 2004) lacking. Longer dosing regimens varied S2). oral cyclophosphamide 50–100 daily) data and, mutagenic potential, agents. Higher doses effective, (Moyo 2002) monthly (Thabet Faisal, toxicity treatment-related significant, HSCT restricted carefully life-threatening review. Fewer 20 European Group Blood Marrow Transplantation (EBMT). prolonged remissions reported, particularly allogeneic (Passweg Rabusin, Procedures Joint Accreditation ISCT EBMT (JACIE)-accredited centres expertise diseases. Warm isolated 0·1–2·7% responds described causing (Grant 1988). SLE. responsive Splenectomy unsuccessful 3/4 1983) 2/3 (Shulman Occasional chemotherapy lymphoma cyclophosphamide. avoid exposure possible exacerbations, dressing protect head, face distal extremities weather. Therapeutic intervention symptomatic circulatory dependence requiring treatment, because sensitised selectively removed spleen. lacking very role. encourage chlorambucil, cladribine, Alpha interferon document eculizumab (Roth 2009), bortezomib 2010) rituximab-bendamustine (Gueli 51% (27/53) 2001), 14/27 2004), 9/20 (primary CHAD) (Schollkopf 2006)] tolerated. However 57–89% relapsed 6·5–11 combined fludarabine, 76% estimated >66 44% grade haematological Iatrogenic cooling, peri- post-operative hypothermia, precipitate patients. Surgery proceed safely careful body Knowing minimum threshold. Elective post-infective suspected. Cardiothoracic cardiopulmonary bypass (CPB) involve paralysis cooling 8–12°C cardioplegia). Clinically might become identified pre-operatively, successful strategies, cardioplegia normothermia employed. intraoperatively pressure (Bracken 1993; Fischer 1997) visible system. undergoing CPB, modifications hypothermia (Jain some, currently during infancy adolescence peak <5 years. self-limiting illness, (Buchanan 1976). predominates frequency triggered viral follows mycoplasma Immunological Evans CVID) cases. pallor, jaundice, tiredness urine. commonly, fever abdominal presented collapse, coma insufficiency sudden, (Aladjidi describ